Project Summary/Abstract It is well established that drug-induced alterations to epigenetic mechanisms that regulate gene expression contribute to the development of drug-seeking behaviors. For instance, both acute and chronic exposure to cocaine increases histone acetylation within the nucleus accumbens (NAc). Furthermore, our lab has identified that the histone acetyltransferase CBP and histone deacetylase HDAC3 are critical regulators of cocaine- associated memory formation. Our work demonstrated that HDAC3 within the NAc negatively regulates cocaine- induced changes in histone acetylation, gene expression, and memory formation. However, it is unknown whether cocaine alters the function of the NAc to promote drug-associative memory by inducing cell-type specific changes in synaptic plasticity and gene expression. The NAc contains two major cell subtypes, divided into two subpopulations of medium spiny neurons (MSNs) based on the expression of receptors, primarily through expression of either dopamine D1 receptors (D1R) or dopamine D2 receptors (D2R). These distinct cell subtypes are known to mediate differential behavioral responses to cocaine, with D1R-MSNs promoting cocaine-seeking. There is substantial evidence demonstrating that cocaine exposure induces differential gene expression within these two subtypes, with increased expression of several HDAC3 target genes in D1R-MSNs. However, it remains an open question as to how HDAC3 activity within these distinct cell types is affected by and regulates drug-seeking. The experiments proposed in this application will allow me to address the overall hypothesis that cocaine-induced disruption of HDAC3 activity within D1R-MSNs promotes acquisition of cocaine-associated behaviors.